The present invention relates to nordihydroguaiaretic acid derivatives, methods of making them and methods of using them for treating viral infections, inflammatory diseases, metabolic diseases, vascular (including cardiovascular) diseases and proliferative diseases, such as cancer.
Nordihydroguaiaretic acid (NDGA, Formula I) has the following chemical structure, in which there are two catechol groups, and a 2,3-dimethylbutane bridge. The butane bridge links two catechol moieties through a 4 position. NDGA is a natural compound that can be isolated from the resin of the leaves of Larrea tridentata, a desert plant indigenous to the southwestern United States and Mexico. It has a meso-form conformation of (2S,3R), which is the symmetric structure, and is not optical active.

Research on NDGA and its derivatives has been attracting increasing interest recently. A large number of NDGA derivatives have been reported, and could be classified as the following:
Type 1: ether bonded NDGA, the most common NDGA derivatives, in which a substituted group is chemically bonded to one or more of the hydroxy groups of the catechol moieties.
Type 2: ester bonded NDGA derivatives, in which a substituted group is covalently bonded to one or more of the hydroxy groups of the catechol moieties.
Type 3: end-ring NDGA derivatives, in which two hydroxy groups at the catechol moieties were linked together to form 5-6 member rings through ether or carbonate bonds.
Type 4: di-substituted NDGA derivatives, in which one hydroxy group of the catechol is methylated, the other one is covalently bonded to a substituted group.
Type 5: phenyl ring modifications, in which the substituted groups are chemically linked to the phenyl ring.
Type 6: Butane bridge modifications, in which two methyl groups in the bridge were removed or modified by substituted groups.
NDGA and its synthetic derivatives have numerous characteristics. Being a lipoxygenase inhibitor, NDGA can induce cystic nephropathy in the rat.1 In addition, it shows various bioactivities, including inhibition of protein kinase C,2 induction of apoptosis,3 alterations of the cellular membrane,4 elevation of cellular Ca2+ level5 and activation of Ca2+ channels in smooth muscle cells,6 breakdown of pre-formed Alzheimer's beta-amyloid fibrils in vitro,7 anti-oxidation,8 etc. This natural product NDGA is used commercially as a food additive to preserve fats and butter in some parts of the world. Recently, the derivatives of the plant lignan NDGA have been used to block viral replication through the inhibition of viral transcription.9-16 These compounds can inhibit production of human immunodeficiency virus (HIV),9-13 herpes simplex virus (HSV),14, 15 and human papillomavirus (HPV) transcripts16 by deactivation of their Sp1-dependent promoters. Moreover, (tetra-O-methyl)nordihydroguaiaretic acid (M4N, Formula II, terameprocol) can function as an anti-HIV proviral transcription inhibitor and causes growth arrest of a variety of transformed human and mouse cells in culture and in mice.17-19 Compound M4N is currently in clinical trials against human cancers.
While M4N (Formula II) is a strikingly effective and non-toxic anticancer agent, M4N and several other methylated NDGAs, all show poor water solubility which somewhat limit their application for certain drug action studies. To circumvent this problem, a water soluble derivative of NDGA, (tetra-O-dimethylglycyl)nordihydroguaiaretic acid (G4N, Formula III) has been designed and synthesized.11, 18

G4N is a very effective mutation-insensitive inhibitor to HIV-1, HSV-1 and HSV-2.17 However, it is somewhat unstable and has a relatively short half-life in aqueous solution, reportedly due to the ester bonds connecting the dimethyl glycine moieties on the NDGA main skeleton.18 
Therefore, there is a need for NDGA derivatives, some with improved water solubility, as well as good stability, both as water soluble compound and as hydrophobic compounds having the desired pharmaceutical effects. The inventors have developed new derivatives of NDGA that have these advantages and will be useful in therapeutic compositions and treatment methods.